cGAS/STING axis mediates a topoisomerase II inhibitor-induced tumor immunogenicity

Checkpoint blockade antibodies have been approved as immunotherapy for multiple types of cancer, but the response rate and efficacy are still limited. There are few immunogenic cell death-inducing (ICD-inducing) drugs available that can kill cancer cells, enhance tumor immunogenicity, increase in vivo immune infiltration, and thereby boost a tumor response to immunotherapy. So far, the ICD markers have been identified as the few immunostimulating characteristics of dead cells, but whether the presence of such ICD markers on tumor cells translates into enhanced antitumor immunity in vivo is still being investigated. To identify anticancer drugs that could induce tumor cell death and boost T cell response, we performed drug screenings based on both an ICD reporter assay and a T cell activation assay. We showed that teniposide, a DNA topoisomerase II inhibitor, could induce high-mobility group box 1 (HMGB1) release and type I IFN signaling in tumor cells and that teniposide-treated tumor cells could activate antitumor T cell response both in vitro and in vivo. Mechanistically, teniposide induced tumor cell DNA damage and innate immune signaling, including NF-[kappa]B activation and stimulator of IFN genes-dependent (STING-dependent) type I IFN signaling, both of which contribute to the activation of dendritic cells and subsequent T cells. Furthermore, teniposide potentiated the antitumor efficacy of anti-PD1 in multiple types of mouse tumor models. Our findings showed that teniposide could trigger tumor immunogenicity and enabled a potential chemoimmunotherapeutic approach to potentiating the therapeutic efficacy of anti-PD1 immunotherapy.
Introduction Cancer immunotherapy has become the major theme of cancer treatment regimens in the last few years, testifying to the genuine capability of the immune control of cancer (1, 2). [...]